This Program Project proposes a multidisciplinary program of research on the pathogenesis of severe combined immunodeficiency (SCID), its variants and Wiskott-Aldrich Syndrome and the distinctive biology of HLA non-identical marrow and fetal tissue transplants applied to their treatment. Particular emphasis will be placed on exploring the limitations and potential of transplants of T cell depleted, HLA-haplotype mismatched marrow for reconstitution of immune function. Specifically, we propose to examine the genetic, cellular and microenvironmental determinants limiting or promoting engraftment, lymphoid differentiation and immunologic functions in patients after transplants of unfractionated HLA identical or compatible marrow, or HLA-incompatible T cell depleted marrow or fetal tissues. Detailed studies of the cellular and genetic bases of graft-host tolerance are also proposed.